Clinician's Quick Reference
`
`Subantimicrobial Dose Doxycycline for Acne
`and Rosacea
`
`Joseph B. Bikowski, MD
`
`From the Department d
`Dermatokgy, Universrly of
`Pittsburgh School of niedidne,
`Pittsburgh, PA
`
`Address for correspondence
`Joseph B. Bikowskt MD,
`SOO ChadMck Street
`Sewicides PA 15143-1851
`&mat
`drh@bikowskimdcom
`
`on psychosocial development and the quality
`of life of those who suffer from it.'
`
`Rosacea is also a common, chronic dermatosis
`estimated to affect at least 1 in 20 people in the
`United States. 6 The majority are fair-skinned,
`Caucasian women, aged 30-50 years old.' One
`community study found 10% of those exam-
`ined had rosacea (14% were women, 5% were
`men).8 Similar to acne, rosacea has a significant
`economic cost6 and psychosocial impact.
`Because the features of rosacea are so visible,
`people with rosacea are often distressed and
`embarrassed about their appearance and may
`exhibit low self-esteem. 9
`
`Acne vulgaris and rosacea present therapeutic
`challenges due to their chronkity, potential for dis-
`figurement, and psychosodal Impact Although
`pathophysiologically distinct. both conditions have
`malor inflammatory components. Consequently,
`topical and systemic anthnkrobial agents are rou-
`tinely prescribed for evtended periods. Emergence
`of resistant strains of Proplonlbacterium acnes,
`adverse events, and compliance Issues associated
`with chronk systemic tetracycline use have led to
`new treatment approaches. At subantimicrobial
`doses, tetracyclines reduce inflammation via anti-
`collagenalytic„ antimatrix-degrading ntetallopro-
`telnase, and cytoklne down-regulating ptoperties.
`Subantimicrobial dose (SD) doxycydine (Perlostat
`20 mg) has dinkal utility in periodontitis and has
`been investigated in a double-blind, placebo-con-
`trolled Vial in the treatment of moderate facial
`acne as well as in an open label study in the treat-
`ment of rosacea. The results of subandmkrobial
`dose doxycydine treatment in early biaLs support
`its benefits and further investigation in acne and
`msacea. (SIUNmed. 2003;2:234-245)
`02003 Le lacq Communkations, Inc.
`
`The Pathogenesis of Acne
`Acne, the major disorder of the pilosebaceous
`unit, presents as noninflammatory (dosed and
`open comedones) and inflammatory (papules,
`pustules, nodules) lesions. Several factors con-
`tribute to the pathogenesis of acne including
`androgens (testosterone and DHEA-S), in-
`creased sebum production, P. aates-driven
`inflammation, and abnormal follicular epithe-
`lial differentiation. Desquamated comified cells
`cne vulgaris is the most common
`of the upper canal of the follicle become abnor-
`chronic skin disorder in the United
`mally adherent Instead of undergoing normal
`ma States, affecting approximately 80% of
`shedding and dischatge through the follicular
`persons at some point between 11 and 30 years
`opening, the cells form a microscopic hypeTker-
`of age.' In 1996 in the United States, the
`atotic plug (the microcomedo) in the follicular
`National Health Interview Survey reported the
`canal, which enlarges and becomes a visible
`prevalence of acne was 26/1000 in persons <45
`comedo. Inflammation (and subsequently,
`years of age.2 Although the data in adults are
`inflammatory acne) is a direct or indirect result
`sparse, one community-based study in England
`of the proliferation of P acnes. Overgrowth of
`found the prevalence of clinical acne in women
`this anaerobic organism, which is otherwise a
`>25 years was 12% and in men it was 3%• 3 In
`normal constituent of the skin flora, occurs in
`addition to the economic costs of physidan vis-
`the lipid-rich environment of the pilosebaceous
`its,4 medications, and om-the-counter treat-
`units containing microcomedones. The host
`ments,5 the disfigurement and permanent scar-
`inflammatory response to P. acnes causes
`ring from acne can also have an adverse impact
`SKINmed: Dermatology for the ainkian (ISSN 1540-9740) is published hi-monthly (Ian.; Mar; May; My; Sept; Nov) by Le !Kg Communications, Inc., Three Parklands Drive, Darien, CT 061
`ht 0 2002 by Le jacq Conununications, inc. All rights reserved. No pan of this pulskation may be reproduced or tranunittedI (cid:9)
`July • Augusi . 2003. or Illechallicat
`PY, recording, or any information storage and retneval system, without permission in writing from the publisher The facts, oOnic (cid:9)
`are those of ti
`I (cid:9)
`aim uu not necessarl reflect those of the Editors or Wisher. For copies in excess of 25 or for commercial purposes, please contact Swei Howell at showetilikfacq.com or 203.656.1711 x106.
`
`1—
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`

`
`damage to and rupture of the follicular wall
`which extends the inflammatory process into
`the surrounding dermis, resulting in the forma-
`tion of the inflammatory lesions (papules, pus-
`tules, and nodules) and ultimately, destruction
`of the collagen matrix in the skin and cyst for-
`mation. Each of these pathogenic processes is a
`potential target for treatment. 1,1°
`
`The Pathogenesis of Rosacea
`Rosacea is a chronic, cutaneous vascular disor-
`der. The earliest manifestations are increased
`and prolonged flushing, erythema, and sensi-
`tive skin. Although the etiology of rosacea
`remains unclear, local irritants (e.g., certain
`topical medications, astringents), wind, tem-
`perature extremes, hot and/or spicy foods and
`beverages, and alcohol can precipitate vasodila-
`tion (flushing) and inflammation (papules, pus-
`tules), the clinical signs of rosacea. 11 In addi-
`tion, the erythema of rosacea is apparently
`aggravated by chronic sun exposure and
`photo damage. Exposing facial skin to sources
`of radiant heat, such as from a fireplace, repro-
`duces the erythema."2
`
`Extravascular fluid from the flushing reaction
`accumulates in the superficial dermis faster
`than the lymphatic vessels can remove it, lead-
`ing to edema and &Image to the lymphatic
`vessels. Elastin degeneration due to actinic
`exposure is probably a common cause of lym-
`phatic failure. The upregulation of proteolytic
`acrivity during inflammation, along with neu-
`trophil infiltration, exacerbates the degrada-
`tion of elastin. Neutrophil elastase and gelati-
`nase, from a variety of cellular sources, are
`capable of degrading the type IV collegen in
`the extracellular matrix on which the integrity
`of the capillary cell wall depends.
`
`Lymphatic failure results in a sustained
`inflammatory response. In a later vascular
`stage, telangiectasias commonly develop on
`the nose, nasolabial folds, and cheeks. The
`condition progresses to an inflammatory
`stage characterized by erythematous papules
`and pustules on the cheeks, forehead, nose,
`and chin. The final stage is the development
`of large inflammatory nodules and connec-
`tive tissue hypertrophy and fibroplasia (a
`result of the accumulation of plasma pro-
`teins). Finally, the fibroplasia may lead to the
`development of rhinophyma (predominantly
`in men)."
`
`Clinician's Quick Reference
`
`Commonly Used Therapy for
`Acne and Rosacea
`Treatment for acne focuses on the resolution
`of inflammation, downregulation of sebum
`production, and elimination of the nonin-
`flammatory lesions manifested as micro-
`comedo and comedones. In rosacea, therapy
`is typically anti-inflammatory in nature. For
`acne, the choice of therapy usually depends
`on the grade and severity. Rosacea therapy is
`determined by the stage."
`
`Mechanism of Action of Antimianblais hi
`Acne. The multifactorial nature of acne ideally
`requires an agent with a variety of 4 4
`mechanisms, exerting an effect
`Tetracyclines diminish
`not only on the bacteria but also
`PMN chemotaxls,
`on the inflammatory host
`reduce lipase pmduc-
`response induced by the bacteria.'
`Certain antimicrobials exhibit
`don in R acnes, down-
`these pleiotropic effects both
`regulate inflammatory
`reducing the numbers of bacteria
`cytokine production,
`and supplessing the host's inflam-
`and inhibit host
`matory response. For example,
`tetracyclines have been shown to:
`collagenolytk activity
`diminish polymorphonuclear
`neutrophil (PMN) chemotaxis
`(possibly by inhibiting PMN
`chemotactic factor); reduce lipase production in
`acnes, resulting in a reduction of fatty adds in
`sebum on the skin surface; 234 affect comple-
`ment pathways; down-regulate inflammatory
`cytokine production; and inhibit host col-
`lagenolytic activity. These pleiotropic properties
`have led to the widespread use of tetracyclines
`for the treatment of acne.
`
`Systemic Antimicrobial Therapy
`Systemic antimicrobial therapy is generally
`more effective than topical therapy presum-
`ably because the drugs penetrate the follicle
`more readily. Oral antimicrobials are indicated
`for persons with moderate-to-severe acne, per-
`sons with inflammatory acne in whom topical
`antimicrobials have failed or are not tolerated,
`persons with involvement of the skin of the
`shoulders, back, or chest (where it is difficult
`to apply topical therapy), and persons with
`mild-to-moderate acne who have a potential
`for substantial scarring or pigmentary changes
`(post inflammatory hyperpigmentation).m
`
`The most common oral antinticrobials used are
`tetracycline Ha, doxycydine, and minocydine.
`The selection of an antimicrobial is typically
`
`SKINmed: Dermatology for the Clinician (ISSN 1540-9740) 4 published bi-monthb , (Jan.; Mar.; May; July; Sept.; Not) by Le jacq Communication% Inc., Three Parklands Drive, Darien, CT 061
`1C,I= ju6, Auq,sf 2063 (cid:9)
`1111 rights refereed. No part this publication may be reproduced or transmitted M any form or by any weans, del:tonic 235 hanic4
`• " (cid:9)
`•
`ose of ti
`I remeval system without permission in writing from the publisher. The facts, opinions and ideas expressed in this publicatio (cid:9)
`and do not necessaray react tncae or the traitors or Pubresluir. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showeBeejacq.com or 203.6.1o. if 11 x106.
`
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`
`Clinician's Quick Reference
`
`guided by the drug's efficacy, safety, convenience
`of use, and cost. The pharmacologic properties of
`doxycycline and minocycline are improved over
`tetracycline HO. They both have improved
`absorption from the gastrointestinal (GO tract
`along with increased lipophilicity resulting in
`better uptake by the pilc6ebaceous unit, and thus
`better tissue penetration than tetracycline HO.
`In addition, their inaeased half-life allows once-
`or twice-daily dosing, potentially facilitating
`patient adherence to the dosing regimen. 18
`
`Efficacy of the Tetracyclines
`in Acne Vulgaris
`There are few well done, placebo-controlled
`clinical trials evaluating the systemic use of
`tetracyclines (especially doxycycline) for the
`treatment of acne. Many studies lack objective
`descriptions of baseline disease severity and
`consistent measures of efficacy and outcome
`between studies, thus making the assessment
`of the relative efficacy of the study drugs even
`more difficult. Despite limitations, overall
`study results and numerous case reports sup-
`port the use of the tetracycline family of drugs
`in the treatment of acne. These studies are
`summarized in Tables I and II.
`
`Efficacy of Tetracydines
`in Rosacea
`Therapy for rosacea malty consists of a combi-
`nation of topical and oral antimicrobials."
`Papules and pustules in msacea are generally
`eliminated with systemic antimicrobials, such as
`tvtracycline HC1, and remission can be main-
`tained to some extent with topical treatment,
`such as metronidazole. 18 Approximately 25% of
`patients relapse within 1 month after discontinu-
`ation of active therapy, approximately 5096 to
`60% at 6 months, and approximately 70% by 1-4
`years in the absence of maintenance therapy. 1417
`The literature concerning rosacea is even more
`sparse than that of ame, but Table III summarizes
`some of the few comparative studies that have
`been done with tetracyclines in rosacea.
`
`Drawbacks of Long-Term
`Standard Dose Therapy
`The Problem of Resistance. The widespread use
`Other Adverse Consequences of LongTerm
`of oral antimicrobials for long-term acne thera-
`Tetracycline Therapy. Based on available infor-
`py has resulted in the development of resistant
`mation, there are more reports of serious adverse
`strains of P. acnes. There is a clear association
`events associated with the use of minocydine
`between the emergence of resistant R crones and
`than with tetracydine HCI or doxycydine. It is
`the therapeutic use of these anthnicrobials. 18•19
`speculated that the difference is related to the
`Resistance of P. acnes to tetracyclines increased
`with the duration of antimicmbial consump- unioye metabolism of minocycline. which has
`SKINmed: Dermatology for the Clinician (MN 1540-9740) is published bi-monthly (Ian.; Mar.; May; July; Sept; Nov.) by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 061
`july • August - 2003 Or mechanicat
`1236 ht C 2002 by Le Oar Communications, inc. AO rights reserved. NO part ot this publication mity be reproduced Or transmitted i (cid:9)
`I (cid:9)
`gay, record or any information storage and retrieval system, without permission in writing from the publisher. The facts, opink (cid:9)
`n are those of
` or 203.656.1711 x106.
`411U UU not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact SarM Howell at sttowelKilleiacq.com
`
`tion,20 demonstrating the effect of an antimi-
`crobial regimen of tetracycline use in acne ther-
`apy on bacterial resistance. 21
`
`Overall resistance of P. acnes to antibiotics had
`increased from 2096 in 1978 to 62% in 1996. 2223
`Levels of resistance to specific antibiotics vary
`widely, but strains resistant to erythromycin,
`dindamydn, tetracycline HO, doxycydine, and
`trimethoprim are the most common. 18 The
`Minimum Inhibitory Concentrations (MICs) of
`tetracycline required to kill 50% of a population
`of R acnes (MIC5(,) are typically higher than M1Cso
`for doxycydine, which are typically higher than
`those of minocydine. Early et al. 2A found that
`tetracycline-resistant organisms were aoss resist-
`ant to doxycydine but susceptible to minocy-
`dine. Because resistance to minocycline was
`rarely observed, minocycline has been the pre-
`ferred tetracycline for use in acne 25 More recent-
`ly, high-level resistance to minocydine (.11050,
`4-16 pg/mL) has been found in populations in
`the UnitEd States. 28 While P. acnes resistance per
`se is not a major public health concern, the abili-
`ty of microbes to pass resistance from one to
`another is well known, and even more important
`is the observation that resistance determinants
`can co-travel, resulting in the potential for spread
`of multiantibiotic resistance with potentially dev-
`astating effects in clinical practice. 1Z27
`
`One strategy designed to minimize the develop-
`ment of resistance is to use a combination of
`topical and systemic therapies with regimens
`that incorporate agents with complementary
`mechanisms of action. Another innovative
`approach is to use a subantimicrobial dose (SD)
`of the antibiotic. As the predominant mecha-
`nism for the development of microbial resist-
`ance is selection of resistant strains over suscep-
`tible strains, a dose could be administered low
`enough that even susceptible strains remained
`unaffected. The exploitation of the anti-inflam-
`matory properties of certain antibiotics might be
`sufficient to elicit a meaningful clinical
`response, and the administration of SDs may
`provide effective therapy without the risk of
`soliciting alterations in microbial susceptibility.
`
`3
`
`Galderma Laboratories, Inc. Ex 2015
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`

`
`NOTICE
`
`!STUDY
`Hersle, 1976
`Mlnocycline vs. placebo;
`43 pts (acne severity
`not specified)
`
`Hubbell, 1982
`Minocycline vs. tetracycline;
`49 pts, grade 2 or 3 pustular
`acne (Pillsbury system)
`
`Leyden, 1982
`Minocycline vs. tetracycline;
`15 pts, moderately severe
`inflammatory acne
`
`Table L. Efficacy of Tetracyclines In Acne Vulgarls—Mlnocycline vs. Placebo and/or Tetracycline
`EFFICACY MEASURES
`1. Total acne load
`Lesions counted and graded (slightly modified) as in luhlin
`study (Table II)
`
`DESIGN
`DB, CO
`Minocycline (n=1 8),
`200 mg x 7 days;
`then 100 mg x 5 wk
`vs.
`Placebo (n=25) x 5 wk;
`then placebo group given
`minocycline and minocycline
`group given placebo x 5 wk
`DB, 6-mo study
`Minocycline (n=25) 50 mg b.i.d.
`vs.
`Tetracycline (n=24) 250 mg b.i.d.
`
`CO, 15 wk
`All pts
`tetracycline 500 mg b.Ld.x 6 wic
`then 3 wk wash-out;
`then minocycline 100 mg bid.
`x 6 wk
`
`After each period, new evaluation and new score expressed
`as 96 of original value
`
`Conversion to grade 1 acne
`Grade 1=occasional profuse comedones, no inflammation
`Grade 2omedones, small superficial pustules and
`inflammation
`Grade 3omedones, small pustules, deeper inflammatory
`lesions
`Effects of tetracycline and minocycline on P. acnes and skin-
`surface lipid levels:
`Complete count inflammatory lesions (face and trunk)
`Quantitative measure P. acnes on forehead and cheek (log
`mean P. acnes/cm2)
`Skin surface lipid levels (ratio FFA/trigly)
`
`•
`
`•
`
`Eady, 1990 (cid:9)
`• Minocycline vs. tetracycline (cid:9)
`•
`25 pts (severity not specified) (cid:9)
`
`6-mo study (cid:9)
`Tetracycline (n=1 2) 500 mg b.i.d. (cid:9)
`vs. (cid:9)
`Minocycline (n=1 3) 50 mg b.i.d. (cid:9)
`
`Changes in numbers of P. acnes on skin surface
`(4.1ogio cfu/cm2 skin);
`Resistance to both tetracycline and minocycline
`Clinical improvement (mean 96 4. acne grade, Leeds
`technique)
`
`Iptsvatients; DB=double-blind; CO=crossover; FFA4ree fatty acids; trigly=triglycerkle; sxs=symptoms; 4.=decrease.
`
`RF.SULTS
`After 5 wks: 4. total acne load;
`Minocychne 4. 40%;
`Placebo 4.1 6% (p<0.05);
`
`After 2nd stage:
`MInocychne (CO) 4. 37%;
`Placebo group 4. 15% (pc0.05)
`
`After 6 months:
`Reached and maintained grade 1
`Minocyctine: 23/25 (92%)
`Tetracydine: 18/24 (75%)
`
`After 6 wks of tetracycline
`Inflammatory lesions 1 52%;
`P. acnes on forehead 4, 22%, cheek 4. 27% (p<0.05);
`Skin surface lipids on forehead 4 87%, cheek 4. 71%
`(p <0.0001 for both)
`After 2nd stage:
`Inflammatory lesions 1 60%;
`P. acnes on forehead 4. 27% (p <0.001),
`cheek 4, 30% (p <0.001 );
`Skin surface lipids on forehead 4. 70% (p <0.001),
`cheek 4 62% (p <0.001 for both)
`After 1 2 wks:
`Minocycline 4. P. acnes 10-fold >tetra (p <0.02)
`After 24 wks:
`Minocycline 4. P. acnes 10-fold >tetra (p <0.05)
`No resistant P. acnes
`After 24 wks:
`Minocycline 5696 4. acne grade
`Tetracycline 65.5% 4. acne grade
`
`4
`
`Galderma Laboratories, Inc. Ex 2015
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`

`
`Table II. Efficacy of Tetracyclines in Acne Vulgaris—Tetracycilne vs. Doxycycline and Doxycycline vs. Placebo or MInocycline
`S111DY
`DESIGN
`BFICACY MEASURES
`RESULTS
`Juhlln, 1969
`DB, CO
`4. Total acne load
`After 4 wk:
`Tetracycline vs. doxycycilne
`T group:
`I Total acne load; Both groups I of 45%
`Lesions graded 1-111:
`28 pts, moderate to severe
`Oxytetracycline 250 mg Ltd. x 4 wk,
`1=nonInflaminatoty, pustule <double pinhead;
`After 12 wIc
`then 250 q.d. x4 vIs,
`acne
`II.pustules >grade !with inflammation;
`T group I of 81%; D group I of 69%
`then doxycyclIne 100 mg evey third day
`111=deep-seated, large Infiltrates;
`vs.
`Lesions on face, neck, trunk, back counted/graded, given
`pointv grade1.1 point; 11=2 points; 111=4 points
`D group:
`Doxycycilne 100 mg q.d. x 4 wk,
`then 100 evety third day x 4 wit, then
`oxytetracycline 250 q.d.
`DB, CO
`Phase I:
`Doxycycline 100 mg q.d. or
`placebo x 4 wk,
`then 4-wk wash-out
`Phase II:
`Placebo and doxycycline switched for
`final 4 wk
`
`Plawig, 1970
`Doxycydine vs. placebo;
`62 pts, inflammatory acne
`
`Total counts of erythematous papules, pustules, and cysts
`96 4 of lesions measured
`Response scores:
`Excellent: >75% I lesions
`Good: 5096-74.9% 4
`Fair 2596-49,996 I
`Poor: no change-24.9% I
`Worsening: T lesions
`
`Phase!:
`Doxycycline 36% 4. (p<.001); placebo 12% T
`Phase It
`Doxycycline 2496 I (p <.05); placebo 296 T
`Individual lesion response
`Comedonet
`Doxycycline & placebo 76% poor
`&RAE
`DoxyclAline 4396 good/excellent; placebo 20% good/exoellent
`Pustules
`Doxycydine 39% good/excellent; placebo 24%good/excellent
`
`Sink, 1978
`Doxycydlne vs. mlnocycline;
`16 pts, severe acne
`
`DB, 12 wk
`Doxycycllne (n=8) 100 mg q.d.
`vs.
`Minocycline (n.8)100 mg q.d.
`Also 5% salicylic acid and 5% resorcinol
`b.i.d.
`
`Harrbon, 1988
`Doxycydine vs. minocyclIne;
`34 acne pts (severity not
`specified)
`
`Observer-B, 12-wk
`Doxycycline (n =, 15) 50 mg q.d.
`vs
`Minocycline (n . 19) 50 mg b.Ld.
`Also 4% chlorhodcline and 5% benzoyi
`peroxide
`
`Olafson, 1989
`Doxycydine vs. minocyclim
`64 pts, moderate to
`moderately severe acne
`
`DB, 12-wk
`Doxycycline (n.33) 50 mg b.Ld. x 4 wk
`vs.
`Minocycline (n. 1) 50 mg b.i.d. x 4 wk,
`then both q.d. x 8 wk
`
`1. In lesion score based on:
`• Extension of se (grades 1-5, E)
`• Seborrhea (grades 0-4,S)
`• Comecbnes (grades 0-4,C)
`• Papules & pustules (grades 0-4,P)
`• Infiltration (grades 0-4,1)
`• Abscess (grades 0-4,A) (grades not described)
`Score= E x (S4C+P+1+A); Max.5 x (4+4+4+4+4).100;
`Min= 0 x (0+0+0+0+0)=0
`Change in no. of nodules, pustules, papules on
`face and back
`Weighted score for active and less active papules=1,
`pustules.4, nodules=10, cysts=15;
`Patient assessed severity as a score out of 100 on a 10 cm
`analog scale;
`Tolerance of treatment and treatment effect scores
`4=excellent, 3=good, 2=fair, 1.poor
`Lesion counts on head, neck, tignkipapulet pustules, and
`open comedones [OC] and dcsed comedones [CCI);
`Patient and physkian assessment of treatment efficacy
`
`• P•Percentages based on interpretation of line graphs, exact numbers not given.
`DB.double-bilnd; CO=crossoven P.placebo; sxs.symptoms; chlorhex.; B= bib,* rx= therapy
`
`Doxycycline 2596 good/excellent; placebo 17% good/excellent
`Doxycycline mean score difference 22;
`Minocycline mean score difference 22.75,
`not statistically significant
`
`I Mean total lesion score (adjusted for differences In baseline severity):
`Doxycycline 66%; minocycllne 68%
`Patient assessment efficacy scores:
`Doxycycline good/excellent 73%;
`MInocyclIne good/excellent 84%
`Patient tolerance scores:
`Doxycycline excellent 53%; minocycline excellent 37%
`
`% LESIONS* (cid:9)
`Dort
`56%
`All lesions (cid:9)
`63%
`Papules (cid:9)
`64%
`Pustules (cid:9)
`42%
`OC (cid:9)
`43%
`CC (cid:9)
`Dozy: 85% MDs and pts said rx effective
`Mino: 87% MDs, 90% Ms said rx effective
`
`MNO
`60
`69
`70
`38
`35
`
`• 4
`
`ILl
`
`5
`
`Galderma Laboratories, Inc. Ex 2015
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782
`
`

`
`Clinician's Quick Reference
`
`Table 111. Efficacy of Tetracycline; in Rosacea
`
`STUDY
`Sneddon, 1966
`Tetracycline vs. placebo;
`78 pts, all degrees of
`severity
`
`Web., 1976
`Doxycycline or
`tetracycline;
`9 pts perioral dermatitis
`(red Papules);
`16 rosacea-like
`dermatitis (all stages);
`19 rosacea
`
`Bikows1d, 2000
`Doxycycline; 2 pts
`rosacea
`
`Torresanl, 1997
`Doxycydine vs. dad;
`40 pts
`
`DESIGN (cid:9)
`
`EFFICACY MEASURES
`
`RESULTS
`
`Tetracydine (1w36) (cid:9)
`250 mg b.i.d (cid:9)
`vs. (cid:9)
`Placebo (n=42) x 4 wk,
`then all tetracycline 250 mg
`b.i.d.
`
`3-yr period (cid:9)
`MI previously brd topical
`fluorinated steroids
`discontinued
`Doxycycline or tetracycline
`(dosage not given) for 2-3 mo;
`concomitant oral prednisolone
`5-15 mg qd for 2-3 wk for
`severe disease;
`19 rosacea pts
`doxycycline 100m9 q.d. +
`topical hydrocortisone x 2 mo
`2 case reports (cid:9)
`Pt 1: 100 mq q.d. continued as
`maintenance;
`Pt 2: 50 mg q.d.; reduced to 50
`mg q.d. for maintenance
`
`Clad (rw23) (cid:9)
`250 mg b.i.d. x 4 wk (cid:9)
`then 250 mg q.d. x 4 wk (cid:9)
`vs. (cid:9)
`Doxycycline (rw1 7) (cid:9)
`100 mg b.i.d. x 4 wk (cid:9)
`then 100 mg q.d. x 4 wk (cid:9)
`
`Disappearance of pustules, flattening of
`papules, diminution of erythema
`(assessment not desaibed)
`
`Assessment measures not described
`
`Assessment measures not provided
`
`Erythema assessed colorimetrics
`Telangectasias (TAE) color prints and
`score 0; 1 (<5 TAE nasolabial sulcus); 2
`(5-10); 3 (10-20); 4 (20-30 + on chin
`and forehead); 5 (>30);
`Pt score efficacy 0 (no efficacy);
`1 (low); 2 (traceable); 3 (mild); 4
`(geed); 3 (high);
`Tolerability score 0 (no SEs); 1
`(occasional); 2 (many sxs); 3 (mild SEs);
`4 (sev SEs); 5 (very sev, discont)
`
`After 1 month:
`Tetracycline 78% improved;
`Placebo 45% improved
`After 2nd month:
`Tetracycline 50% improved;
`Placebo (now bal with
`tetracycline) 74% improved
`7/9 with perioral dermatitis =
`healing and full remission
`14/16 rosacea-like dermatitis =
`healing and full remission
`14/19 rosacea = clinical
`improvement
`5 = complete cure
`
`Pt 1: cleared eruptions in 9 wk;
`Pt 2: marked 1 erythema +
`lesions after 4 wlcs; in follow-up
`deared (time not given);
`Continued clearing of
`inflammatory lesions at 6- mo
`follow-up in both pts
`After 8 wk:
`Erythema: mean value
`Clan 4.8-5.8
`Doxycycline 3.8-5.2
`TAEs: i mean score 3.8-2.2
`Papules: 4, mean score 3.8-0.2
`Pustules: I mean score 3.8-0.2
`Efficacy mean score:
`Clad: 4.8
`Tolerability
`Doxycydine: 4.2
`Clad mean SCAM: 0.32 (occas SEs)
`Doxycydine mean score:
`1.06 (mild SB)
`
`Clar-Clarithromydn; txdvresaibed; SE=side effect sevevere; discontliscontinued
`
`an amino add side chain with potential to form
`a reactive metabolite. Neithez tetracycline HC1
`nor doxycycline contains the amino add side
`chain; therefore, the hypersensitivity reactions
`associated with minocydine may be specific to
`this antimiaobia1.28 In vitro studies have
`demonstrated the presence of a minocycline-glu-
`tathione conjugate when minocycline is incu-
`bated with hypochlorous acid, as is found in
`neutrophils. When a reactive metabolite is gen-
`erated, glutathione transferase acts to detoxify
`this product The presence of minocydine-
`glutathione conjugates implies the formation of
`potentially toxic metabolites. These potentially
`reactive metabolites generated by minocydine
`may bind to tissue macromolecules causing cell
`damage directly, or they may act as haptens,
`eliciting a secondary immune response?)
`
`Adverse Events Associated With
`Acne Therapy
`Tetracyclines as a Class of Antlinkroblais. GI
`disturbances (nausea, vomiting, and diarrhea)
`are the most common side effects associated
`with all the tetracyclines. All tetracycline
`antimicrobials carry warnings of phototoxici-
`ty reactions, manifested as an exaggerated
`sunburn reaction. To date, there have been no
`double-blind, controlled studies showing that
`tetracycline HC1 is a photosensitizer. Mino-
`cycline is generally regarded as the least pho-
`tosensitizing of the tetracycline derivatives at
`the commonly administered dose."
`
`Prescribing information for all tetracyclines
`warns that they can cross the placenta and
`have shown evidence of embryotoxidty with
`
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`C (cid:9)
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`6
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`
`Clinician's Quick Reference
`
`toxic effects on the developing fetus.
`Minocydine has been shown to have a car-
`cinogenic metabolite, although the clinical
`relevance of this finding is unknown. 31
`
`Tetracycline NCI. Tetracycline HC1 has been
`implicated in an increased incidence of
`esophageal ulceration, 32 particularly when
`administered in capsule form. The use of
`tetracycline HC1 has also been associated with
`the development of pseudotumor cerebri in
`adult and pediatric patients33 and in patients
`receiving concomitant isotretinoin therapy. 34
`
`Doxycycline. Esophageal irritation has been
`seen with doxycydine hyclate, which dis-
`solves at a pH of 2-3. In contrast, the pH on
`dissolution of the newer salt, doxycycline
`monohydrate, is 5-6, resulting in no esopha-
`geal irritation and less GI upset. 15
`
`Photosensitivity can be seen with doxycycline
`therapy. The relationship is dose dependent,
`and phototoxidty occurs in 3% of patients tak-
`ing 100 mg/day. This can be a problem clinical-
`ly because patients who do not respond to stan-
`dard doses may be taking maintenance therapy
`doses in excess of 100 mg/day, which greatly
`increases the potential for phototoxic eruptions
`(20% at 150 mg and 42% at 200 mg/day). 35
`
`Because these drugs are given long-term for
`acne and msacea, the possibility for carcino-
`genic potential is also of concern. Recently, dur-
`ing the development of a SD of doxycycline as
`a chronic, adjunctive therapy for the treatment
`of adult periodontitis, this issue was systemati-
`cally addressed for the first time. The labeling
`for this drug (Periostat) states that the carcino-
`genic potential of doxycycline has been investi-
`gated with no findings of changes indicating a
`direct carcinogenic effect. Increases in benign
`fibroadenomas of the breast, polyps of the
`uterus, and adenoma of the thyroid, which are
`consistent with a hormonal effect, were
`observed in treated women. Doxycydine has
`shown no mutagenic activity and no convinc-
`ing evidence of clastogenic activity. 36
`
`Minocycline. The vestibular side effects of
`lightheadedness, loss of balance, dizziness, or
`true vertigo in patients taking minocydine
`are well known and occur more often in
`women.37,38 These effects arise because the
`lipophilicity of minocycline results in some
`
`degree of blood-brain barrier penetration.
`
`Hyperpigmentation or a blue/black skin or
`mucous membrane discoloration has been
`found with long-term use of minocy-
`cline.39," In rare cases, such hyperpigmenta-
`tion may occur within 1 month of minocy-
`dine therapy. There are two types: localized
`pigmentation occurring at the site of previ-
`ous inflammation, and a more generalized
`diffuse pigmentation. 41
`
`Although rare, a variety of drug-induced syn-
`dromes have been described in patients taking
`minocydine for acne. Drug-induced lupus and
`hepatitis are the most common reactions and
`except for serum sickness (mean time to occur-
`rence 16 days); these syndromes typically pres-
`ent after prolonged use (mean time to occur-
`rence: 25.3 months). 42.43 Coexistent minocy-
`dine-induced lupus erythernatosus and autoim-
`mune hepatitis after long-term use (4-120
`months) occurred at dose ranges of 50-200
`mg/day." Hepatitis with minocycline use is
`most often associated with hypersensitivity syn-
`dromes or delayed autoimmune hepatitis.4015
`
`Case reports of pneumonitis," lymphadenopa-
`thy, and an infectious mononucleosis-type
`reaction47 have been reported. Rare cases of
`pseudotumor cerebri (idiopathic intracranial
`hypertension)" associated with long-term
`minocycline treatment (4 weeks-18 months)
`have occurred:IL" Long-term administration
`in rat studies resulted in evidence of thyroid
`tumor production and thyroid hyperplasia in
`rats and dogs.31 Based on reports of adverse
`drug reactions, Gough et aL 5° recommended
`that safer alternatives than minocycline should
`be considered for treating acne.
`
`A New Therapeutic Option-
`SD Doxycydine
`Within a decade of their discovery in 1947,
`tetracyclines were widely used as anti-infec-
`fives and for the treatment of acne. 51 Steadily
`increasing rates of bacterial resistance limited
`their use for many infections. In 1983, Golub
`reported on a seminal study in rats in which
`minocycline inhibited tissue collagenolytic
`enzyme activity by mechanisms independent
`of its antibacterial activity. 52 This finding
`spawned an extensive series of experiments
`to elucidate the nonanthnicrobial properties
`of tetracyclines, suggesting a new therapeutic
`
`SICINmed: Dermatobgy for the Clinician (ISSN 1540-9740) is published bi-monthty (Jan.; Mar.; May; My, Sept; Nov) by Le jacq Communications, Inc., Three Parldands Drive, Darien, Cr 061
`1240 ht 02002 byle jacq Communications, inc. AO rights reserved